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Review paper

Jarosław Woroń1, Iwona Filipczak-Bryniarska2, Jerzy Wordliczek2 1Chair of , Department of Clinical Pharmacology, Jagiellonian University College of Medicine, Kraków 2Department of Pain Treatment and Palliative Care, Jagiellonian University College of Medicine, Kraków

Undesirable drug in palliative medicine

Abstract The importance of drug in palliative care is acquiring more and more practical importance. In the polytherapy used in palliative care, drugs can induce a number of interactions and increase the risk of unwanted drug reactions. This paper discusses the importance of drug-drug interactions in clinical practice.

Key words: palliative care, pharmacotherapy, drug interactions

Adv. Pall. Med. 2008; 7: 81–88

Introduction pair organ functions crucial for the pharmacokinet- ics of drugs. The occurrence of undesirable post- The importance of the interaction of the drugs drug effects is an additional risk factor. Hypoalbu- used in palliative medicine is acquiring more and minaemia is observed in the majority of patients, more practical importance. The patient with advanced which is important in drugs with a close affinity to disease often obtains a few drugs at the same time, albumins. In such situations, a free drug fraction which may enter into unfavourable interactions, both increase is observed in the drugs, which increases pharmacokinetic and pharmacodynamic, resulting in the risk of undesirable effects. undesirable consequences. Another practical prob- lem is the fact that drugs administered simultaneously Interaction with drugs used may have a shared profile of undesirable effects with in palliative pain therapy the capacity to increase. The general condition of the patient with ad- Interactions with non-steroidal vanced disease repeatedly undergoes dynamic anti-inflammatory drugs (NSAIDs) changes, which cause new symptoms to appear. Non-steroidal anti-inflammatory drugs are one Thus, distinguishing which of the symptoms is the of the most frequently used type of drug in pallia- result of the progression of the disease and which tive medicine. With regard to how they suppress may result directly from the undesirable effects of prostaglandin synthesis, they may enter into un- the drugs used is an important element in evaluat- favourable pharmacodynamic interaction with drugs ing the patient's status. used in the pharmacotherapy of cardiovascular sys- Palliative patients were once frequently treated tem diseases (angiotensin-converting inhib- with chemo- and hormonotherapy, which may im- itors, AT1 antagonists, beta-adrenolytics,

Address for correspondence: dr Jarosław Woroń Chair of Pharmacology, Collegium Medicum of Jagiellonian University ul. Medyczna 9, 30–688 Kraków Tel./faks: (+48 12) 657 54 56/657 02 62 e-mail: [email protected] Advances in Palliative Medicine 2008, 7, 81–88 Copyright © 2008 Via Medica, ISSN 1898–3863

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especially and ), loop , Table 1. Drugs suppressing CYP2C9 activity and the result of this interaction is to limit the effec- Drugs tiveness of circulatory drugs and diuretics [1]. It is worth mentioning that patients with impaired re- nal function who take NSAIDs and loop diuretics simultaneously have an increased risk of nephrotox- icity. It is important for the risk of interaction that the majority of NSAIDs bind with blood proteins to a high degree (over 90%). Consequently, special care should be taken when simultaneously using other Clopidogrel drugs (sulphonylourea derivatives, oral anticoagu- Fluconazole lants, or anti-epileptics) which bear a NSAID-like affinity for albumins. The clinical effect of these in- teractions is an increase in the free fraction of drugs Table 2. Drugs inducing CYP2C9 activity displaced by NSAIDs and the occurrence of undesir- Drugs able effects. Cyclofosfamide A frequent mistake observed in clinical practice Ifosfamide is the simultaneous administration of two or even Valproic more NSAIDs. It should be remembered that this does not lead to the synergism of an ef- fect but significantly increases the risk of gastrointes- cytes. may directly damage hepatocytes, tinal toxicity, and and damage. One of which should be considered if the patient requires the major undesirable effects of NSAIDs is drug- other potentially hepatotoxic drugs. induced gastropathy. This risk increases when the With patients aged 65 and older, NSAIDs should patient simultaneously takes other drugs which may be very cautiously coadministered with angiotensin- damage the upper part of the digestive tract, in converting enzyme inhibitors and loop diuretics be- particular: cause this combination in such patients leads to — glucocorticosteroids; renal function impairment. Caution should be used — oral bisphosphonates; during the co-administration of NSAIDs with anti- — oral ; platelet drugs, owing to the increased risk of blood — drugs from the group of in loss. hibitors, which not only inhibit the reuptake of Some NSAIDs (diclofenac, , , serotonin in the structures of the central ner- ) are actively metabolized by the CYP2C9 vous system but also suppress this uptake to isoenzyme: their use introduces an increased risk of platelets; pharmacokinetic interaction with other drugs which — , which inhibits fibrosis processes inhibit or activate this isoenzyme. that accompany the healing of digestive tract The most frequently used drugs in clinical prac- damage and are induced by NSAIDs. tice which induce the activity of the CYP2C9 isoen- Moreover, the combination of NSAIDs with zyme are presented in Table 1 [3]. Drugs that sup- spironolactone may cause hyperkalaemia. press its activity, and thus extend the half-life of The use of drugs from the H2 receptor antago- the above-mentioned NSAIDs, are presented in Ta- nist group while NSAIDs are administered is a mis- ble 2. take. H2 blockers do not protect the digestive tract from being damaged by NSAIDs but mask the symp- Interactions with toms of this damage [2]. Metamizole should be cautiously co-adminis- In a clinical situation, when the administration tered with neuroleptics and deriva- of gastric acid secretion inhibiting drugs together tives due to the risk of severe hyperthermia. with NSAIDs is necessary, proton pump inhibitors Metamizole increases the concentration of meth- are the best choice. otrexate in blood serum, increasing its toxicity. Re- Care in the use of NSAIDs should be taken in cent literature suggests that metamizole can induce patients with liver damage because these drugs may the CYP3A4 isoenzyme , which means that it could induce oxidative stress in hepatocytes, cause dam- decrease the effectiveness of the of age to the mitochondria and apoptosis of hepato- drugs such as some , ,

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, , , and glu- result, the pharmacologically O- cocorticosteroids. demethyl tramadol (M1) is formed. For this rea- son, the simultaneous administration of tramadol Interactions with paracetamol with drugs inhibiting the activity of CYP2D6 (Table Paracetamol is metabolized by the 1A2 isoen- 3) is not recommended: on the one hand it inhibits zyme of P450 cytochrome. For this reason it should the formation of the active metabolite but on the be cautiously co-administered with drugs which in- other it may lead, especially when forms with pro- hibit the activity of this isoenzyme. This is of special longed action are used, to undesirable and even practical importance when co-administered with toxic symptoms. We must bear in mind that 5–10% , , fluvoxamine and ticlo- of the Caucasian population slowly metabolize drugs pidine. Paracetamol increases the kidney's elimina- with the CYP2D6 isoenzyme, and thus in these pa- tion of prostaglandins and decreases plasma renin tients the risk of undesirable pharmacokinetic inter- activity. Consequently, it may imitate the actions is additionally increased. Tramadol, apart effect of loop diuretics. from its influence on receptors, also inhibits serotonin reuptake in the descending antinocicep- Interactions with codeine tive system, which causes an increased risk of sero- Codeine co-administered with , tonin syndrome. , , , , Caution should be taken when co-administering benzodiazepines and neuroleptics has a synergistic tricyclic antidepressants ( in particular) depressive influence on the central nervous system. and serotonin reuptake inhibitors (fluoxetine and When simultaneously administered with other opio- paroxetine in particular), because while such a com- ids, the risk of respiratory depression increases. bination inhibits the metabolism of tramadol, it also Codeine undergoes hepatic metabolism under increases the risk of seizure and . the influence of the 2D6 and 3A4 isoenzymes of The use of as an dur- P450 cytochrome. For this reason, caution should ing tramadol therapy is also unfavourable. Meto- be taken when co-administering drugs inhibiting clopramide is a strong inhibitor of tramadol metab- the activity of the above-mentioned isoenzymes. olism. Drugs of the most clinical importance with the ca- Tramadol increases the depressive action of hyp- pacity to inhibit CYP2D6 and CYP3A4 isoenzymes notics, derivatives and neuroleptics are presented in Table 3. on the CNS. When co-administered with neuroleptics, it may cause seizures. Using tramadol with hypoten- Interactions with tramadol sive drugs increases the risk of [4]. Tramadol undergoes hepatic metabolism un- der the influence of the CYP2D6 isoenzyme. As a Interactions with Nefopam should not be used with tricyclic anti- depressants because of the risk of hyperthermia, Table 3. Drugs suppressing CYP2D6 and CYP3A4 severe hypertension and arrhythmia. Nefopam in- activity hibits serotonin and noradrenalin reuptake and for CYP2D6 CYP3A4 this reason increases the potency of cholinolytic and Metoclopramide serotonin reuptake inhibitors: sympathomimetic drugs. Amitriptyline fluoxetine, paroxetine, sertraline -containing drugs (Normatens) inhibit Ciprofloxacin the analgesic action of nefopam. Fluoxetine Norfloxacin Drugs should be used cautiously with benzodi- Paroxetine azepine derivatives, hypnotics and first-generation Erythromycin drugs. Anastrozole Interactions with Doxorubicin Buprenorphine increases the depressive influence Lanzoprazole of tricyclic antidepressants and neuroleptics on the Methadone Methadone CNS. Used with other , it increases the risk Valproic acid Methylprednisone of depression of the central nervous system. By de- Valproic acid creasing saliva secretion, cholinolytic drugs may Werapamil hamper sublingual administration.

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Interactions with toxicity of this mixture and the increased risk of Dihydrocodeine should be used cautiously in bradycardia, sleep disruption, depression, urinary patients taking MAO inhibitors. In people with ge- retention and the depression of cough and respira- netically determined rapid , simul- tory centres. taneous administration decreases the an- Caution should also be used when co-adminis- algesic effect of the drug. tering methadone with tricyclic antidepressants (TCA) because methadone disturbs their metabo- Interactions with lism, inhibiting the activity of the CYP 2D6 isoen- Morphine acts synergistically with drugs with a zyme. depressive action on the central nervous system. However, , , rifampi- Morphine increases the action of anticoagulants. cin, risperidone and glucocorticosteroids suppress Morphine is metabolized by UDPG 2D7 and CYP2D6 the analgesic action of methadone, probably be- isoenzyme of P450 cytochrome and its metabolism cause of interactions with CYP3A4. can be inhibited by CYP2D6 inhibitors (see Table Methadone may disrupt the metabolism of beta- 3). As a result of morphine metabolism, the risk of adrenolytics, neuroleptics and weak opioids (co- undesirable effects is increased [5]. deine, dihydrocodeine, tramadol), increasing the risk Metoclopramide increases morphine absorption of undesirable effects [6]. from the digestive tract and intensifies its effect. Tricyclic antidepressants, and Interactions with amitriptyline in particular, cause the prolongation Ketamine increases the activity of myorelaxants. of the half-life of morphine. Morphine and cimeti- It should be co-administered cautiously with alpha dine preparations should not be administered si- and beta adrenolytics and calcium antagonists, ben- multaneously because of the increased risk of respi- zodiazepine derivatives and opioids, due to the risk ratory depression, as cimetidine can inhibit mor- of heart failure. phine metabolism. Ketamine used with aminophilin decreases the Caution should be taken when simultaneously convulsant threshold. administering morphine and benzodiazepines be- cause this combination increases the risk of respira- Interactions with tory depression. This concerns the co-administra- Dextromethorphan is metabolized with the CYP tion of morphine and in particular, which 2D6 isoenzyme and its use with drugs inhibiting introduces analgesic action via an opioid receptor the activity of this isoenzyme (Table 3) increases the of the mu type. risk of respiratory depression, and dizziness. Dextromethorphan intensifies the effects of sed- Interactions with fentanyl atives, hypnotics, neuroleptics and benzodiazepine Fentanyl increases the depressive influence of derivatives on the CNS structures. hypnotics on the CNS, , benzodiazepine derivatives and antihistamine drugs transferring to Interactions with the CNS. Fentanyl is metabolized by the 3A4 isoen- Amantadine increases the undesirable effects of zyme and drugs which inhibit the activity of this drugs, you need a conjunction here isoenzyme can increase the risk of adverse drug re- to link these statements cotrimoxazol decreases the actions (see Table 3). renal of amantadine, increasing the risk of undesirable effects. Hydrochlorothiazide increas- Interactions with methadone es plasma amantadine concentration. Methadone is metabolized by the CYP 3A4 isoen- zyme, hence caution should be taken when com- Interactions with antidepressants used in bining drugs inhibiting its activity (Table 3). Metha- pain pharmacotherapy done metabolism inhibition may cause bradycar- Of the antidepressants used in pain pharmaco- dia, mood swings, depression of the respiratory cen- therapy, tricyclic antidepressants, , mi- tre and an increased risk of potentially lethal ar- anserin, mirtazapine and venlafaxine have found rhythmia, which are linked to QT prolongation in clinical use. ECG. The interactions with serotonin reuptake inhibi- Methadone should be cautiously combined with tors (SSRIs) will not be discussed further in this pa- benzodiazepine derivatives due to the significant per, due to the minor importance of this group of

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Table 4. Interactions with antidepressants Drug/group of drugs Interaction with other simultaneously administered drugs Tricyclic antidepressants (TCA) Amitriptyline and clomipramine, the most frequently used drugs from the TCA group, are metabolized with the participation of multiple isoenzymes of P450 cytochrome. Consequently, there is a significant risk of unfavourable pharmacokinetic interaction. Amitriptyline is metabolized by 2D6, 3A4, 1A2, 2C9 and 2C19 isoenzymes, and clomipramine with 3A4, 1A2, 2C19 isoenzymes. Drugs suppressing the activity of the above-mentioned isoenzymes will inhibit the metabolism of TCAs, increasing the risk of undesirable effects. TCAs may increase the potency of sympathomimetics, causing an increase in blood pressure. Due to the strong cholinolytic effect, TCAs inhibits peristal sis of the digestive tract and may thus impair the absorption of orally administered drugs. Clomipramine, the most serotoninergic drug amongst TCAs, may be a cause of serotonin syndrome as a result of pharmacodynamic interaction with other drugs that increase serotoninergic transmission. Doxepine Should not be co-administered with QT-prolonging drugs in ECG, as it increases the risk of potentially lethal arrhythmia. Doxepine increases the depressive action of other sedatives, anxiolytics, antidepressants and neuroleptics on the CNS. Phenothiazine neuroleptics increase the cholinolytic effect of doxepine. Mianserin Acts synergistically and depressively with anxiolytics, hypnotics and sedatives on theCNS. Mirtazapine Increases the sedative effect of benzodiazepine derivatives. Venlafaxine Metabolized by 2D6 and 3A4 isoenzymes of P450 cytochrome. Thus co-administration with drugs inhibiting activity of these isoenzymes (Table 3) should be avoided. Caution should be used in simultaneously administering venlafaxine with tramadol and other drugs of serotoninergic effect due to an increased risk of serotonin syndrome.

Table 5. Interaction with anti-convulsants used in pain pharmacotherapy Drug Interaction with other simultaneously administered drugs Valproic acid Valproic acid increases plasma carbamazepine concentration, carbamazepine decre- ases plasma valproic acid concentration. Valproic acid increases the effect of antide- pressants, neuroleptics and oral anticoagulants. If co-administered with , idiopathic epilepsy may occur. Should be cautiously administered with drugs bearing a strong affinity for blood proteins, due to the ability to increase free drug fraction. Carbamazepine Drugs whose concentration increases after simultaneous administration with carbam- azepine, leading to an increase in the risk of unfavourable effects: , diltiazem, fluoxetine and isoniazide. Carbamazepine may decrease the therapeutic effectiveness of oral anticoagulants, clonazepam, alprazolam, corticosteroids, cyclosporine, , doxycycline, oestrogens and gestagens. When co-administered with thiazides and/or , hyponatraemia may occur. decreases plasma carbamazepine concentration. Carbamazepine acts synergistically with neuroleptics. However, it must not be forgotten that the risk of toxicity increases with such a combination. Hypnotics increase drowsiness and ataxia after gabapentin. Drugs from the group decrease gabapentin absorption from the digestive system. Morphine increases gabapentin blood concentration. Increases the effect of .

drugs as co-. Interactions with antidepres- tin and pregabalin. Interactions with these drugs sants that are important from a practical point of are presented in Table 5. view are shown in Table 4 [7]. Interactions with relaxants: hyoscine Interactions with anti-convulsants used in butylbromide , , drotaverine palliative care The cholinolytic effect of hyoscine is increased Drugs of the greatest practical importance in by TCAs, benzodiazepines and neuroleptics. Hyos- pain pharmacotherapy with neuropathic compo- cine intensifies the effect of drugs causing CNS de- nents are valproic acid, carbamazepine, gabapen- pression and suppresses the effect of

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antagonists on intestinal peristalsis. Papaverine and diabetics and anticoagulants. Combined with drotaverine may intensify the effect of hypotensive NSAIDS, they increase the risk of bleeding in the drugs. upper part of the digestive tract. When co-adminis- tered with diuretics, they increase the loss of potas- Interactions with neuroleptics sium ions. Barbiturates and anti-epileptics decrease the ef- The most frequently used neuroleptics are halo- fect of glucocorticosteroids. peridol, and risperidone. Interactions with drugs used in the Interactions with haloperidol treatment of nausea and Haloperidol increases the depressive action of opioids, benzodiazepines, barbiturates and TCAs on Interactions with metoclopramide the CNS. Valproic acid and oral anticoagulants in- Metoclopramide decreases (digoxin) or increas- tensify the effect of haloperidol. Haloperidol increas- es (NSAIDs, paracetamol, cyclosporine, levodopa) es the cholinolytic effect of other simultaneously drug absorption from the digestive system. Due to administered drugs. It increases the action of hy- its central action, metoclopramide intensifies the potensive drugs, except to which it acts depressive action of benzodiazepine derivatives and antagonistically. TCAs on the CNS. It may increase opioid analgesia. As for hypotension in patients treated with ha- Cholinolytic drugs decrease the effect of metoclo- loperidol, should not be used due pramide. Metoclopramide is a strong inhibitor of to the risk of a paradoxical and further decrease of the 2D6 isoenzyme of P450 cytochrome and inhib- blood pressure. Haloperidol should not be co-ad- its the metabolism of codeine and tramadol. ministered with salts due to the risk of respiratory depression and hypotension. Interactions with Thiethylperazine increases CNS depression when Interactions with levomepromazine co-administered with benzodiazepine derivatives Drugs of cholinolytic effect intensify the anti- and opioids. effect of levomepromazine. CNS depress- ing drugs, including opioids, co-administered with Interactions with , levomepromazine introduce a synergic suppressing and effect on CNS functions. When co-administered with These do not enter into clinically important in- hypotensive drugs it can cause orthostatic hypoto- teractions with other simultaneously administered nia. Levomepromazine can induce unwanted drug . interactions with procholinergic drugs such as me- toclopramide. Interactions with bisphosphonates (clodronate, pamidronate, zolendr- Interactions with risperidone onate) and calcitonin Risperidone can increase the effect of drugs that have a depressing effect on the CNS. Carbamazepine Bisphosphonates co-administered with glucocor- decreases plasma risperidone concentration. TCAs ticosteroids and calcitonin increase the risk of hy- and increase plasma risperidone pocalcaemia. Oral bisphosphonates given with concentration, increasing the risk of undesirable ef- NSAIDs increase the risk of damage to the upper fects. A similar effect is observed in fluoxetine and part of the digestive tract. paroxetine. Drugs in the form of oral solutions should Calcitonin does not interact with other simulta- not be drunk with tea and drinks such as -Cola, neously administered drugs. because these drinks can decrease risperidone ab- sorption from the gastrointestinal tract. Conclusion

Interactions with glucocorticosteroids As presented above, appropriate polytherapy is of key importance for pharmacotherapy in pallia- , methylprednisolone and pred- tive medicine. nisone are metabolized with CYP 3A4, which can be Prevention of unfavourable drug and post-drug induced simultaneously by CYP 3A4 inducers. Glu- interactions should be an inseparable element of cocorticosteroids suppress the effect of oral anti- responsible treatment.

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